Study shows Where Alzheimer's starts and how it spreads

Using high-resolution functional MRI (fMRI) imaging in patients with Alzheimer's disease and in mouse models of the disease, Columbia University Medical Center (CUMC) researchers have clarified three fundamental issues about Alzheimer's: where it starts, why it starts there, and how it spreads.

In addition to advancing understanding of Alzheimer's, the findings could improve early detection of the disease, when drugs may be most effective. The study was published today in the online edition of the journal Nature Neuroscience.

"It has been known for years that Alzheimer's starts in a brain region known as the entorhinal cortex," said co-senior author Scott A. Small, MD, Boris and Rose Katz Professor of Neurology, professor of radiology, and director of the Alzheimer's Disease Research Center. "But this study is the first to show in living patients that it begins specifically in the lateral entorhinal cortex, or LEC. The LEC is considered to be a gateway to the hippocampus, which plays a key role in the consolidation of long-term memory, among other functions. If the LEC is affected, other aspects of the hippocampus will also be affected."

The study also shows that, over time, Alzheimer's spreads from the LEC directly to other areas of the cerebral cortex, in particular, the parietal cortex, a brain region involved in various functions, including spatial orientation and navigation. The researchers suspect that Alzheimer's spreads "functionally," that is, by compromising the function of neurons in the LEC, which then compromises the integrity of neurons in adjoining areas.

A third major finding of the study is that LEC dysfunction occurs when changes in tau and amyloid precursor protein (APP) co-exist. "The LEC is especially vulnerable to Alzheimer's because it normally accumulates tau, which sensitizes the LEC to the accumulation of APP. Together, these two proteins damage neurons in the LEC, setting the stage for Alzheimer's," said co-senior author Karen E. Duff, PhD, professor of pathology and cell biology (in psychiatry and in the Taub Institute for Research on Alzheimer's Disease and the Aging Brain) at CUMC and at the New York State Psychiatric Institute.

In the study, the researchers used a high-resolution variant of fMRI to map metabolic defects in the brains of 96 adults enrolled in the Washington Heights-Inwood Columbia Aging Project (WHICAP). All of the adults were free of dementia at the time of enrollment.

"Dr. Richard Mayeux's WHICAP study enables us to follow a large group of healthy elderly individuals, some of whom have gone on to develop Alzheimer's disease," said Dr. Small. "This study has given us a unique opportunity to image and characterize patients with Alzheimer's in its earliest, preclinical stage."

The 96 adults were followed for an average of 3.5 years, at which time 12 individuals were found to have progressed to mild Alzheimer's disease. An analysis of the baseline fMRI images of those 12 individuals found significant decreases in cerebral blood volume (CBV) — a measure of metabolic activity — in the LEC compared with that of the 84 adults who were free of dementia.

A second part of the study addressed the role of tau and APP in LEC dysfunction. While previous studies have suggested that entorhinal cortex dysfunction is associated with both tau and APP abnormalities, it was not known how these proteins interact to drive this dysfunction, particularly in preclinical Alzheimer's.

Comments

This is very important study with many outstanding findings. I find the link and joint function between tau and APP particularly interesting

3 Replies

Author: Guest

Posted: 2013-12-23

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It is promising that this new imaging method, a high-resolution form of functional magnetic resonance imaging, could also be used to assess potential new drug treatments at early stages of the disease

2 Replies

Author: Guest

Posted: 2013-12-23

+1

APP is precursor of amiloid. We knew that amyloid beta is a good target. It's been the focus of Alzheimer's research-the protein is a hallmark of the disease, forming distinctive clumps of sticky plaque in the brains of people with Alzheimer's- we are building on this with these new discoveries
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Author: Guest

Posted: 2013-12-23

+0

There are more than 20 different proteins that can misfold and form amyloid, which is why there are many different types of systemic amyloidosis- serious disease in each case. Scans could help here also
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Alzheimer's disease is a serious problem and new approaches for treatment could help. It is most common cause of dementia linked to a set of symptoms which can include loss of memory, mood changes, and problems with communication and reasoning.
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Author: Guest

Posted: 2013-12-23

+1

This topic is important and recognised. Recently, leading nations have committed to developing a cure or treatment for dementia by 2025 at the G8 dementia summit.
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Author: Guest

Posted: 2013-12-23

+0

Dementia has been linked to diabetes recently. So, lifestyle improvements should also be considered

1 Replies

Author: Guest

Posted: 2013-12-23

+0

The fact that so many diseases are caused by bad lifestyle is pointing that either the message is not going through or that people are not sure that it is right
Reply